Cocaine addiction has reached epidemic proportions in the U.S. over the past two decades. Although much research has focussed on the psychopharmacological and cardiovascular effects of acute cocaine treatment, few studies have examined the effects of chronic cocaine abuse on endocrine function. A number of clinical reports have appeared suggesting that chronic cocaine abuse results in a disruption of reproductive function. The few animal studies in the literature suggest that cocaine suppresses circulating levels of plasma testosterone in male rats. Our preliminary data demonstrate a drastic reduction in serum T concentrations to castrate levels, without a decrease in serum LH concentrations. The lack of an increase in circulating luteinizing hormone levels accompanying the cocaine-induced fall in testosterone and cocaine-induced suppression of the male specific hepatic cytochrome P450 isozyme CYP 2Cll, suggests multiple sites of cocaine action; 1) at the level of the hypothalamus and/or pituitary, involving changes in responsiveness to steroid feedback and in patterns of growth hormone secretion, and 2) the gonads, involving a direct cocaine effect on gonadal steroid biosynthesis. The current application proposes to examine in detail the molecular mechanisms underlying the cocaine-induced impairment of the endocrine systems of reproduction and growth. This proposal focusses on disruption of sex steroid metabolism, since levels of circulating androgens and estrogens modulate hypothalamic and pituitary hormone secretory profiles, and the pattern of these circulating hormones, especially growth hormone and luteinizing hormone, regulate both gonadal steroid biosynthesis and hepatic gonadal steroid degradation. Thus, gonadal steroids serve as the functional link in the hypothalamo-pituitary-gonadal axis and the liver. These studies will be conducted using state-of-the-art methodology including; pulsatile hormone analysis, radioimmunoassay, Western blot analysis, Northern blot analysis, push/pull perfusions and enzyme assays.